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Aberrant energy and substance metabolic pathways of tumor cells critically support tumor cell proliferation by hijacking the resources from nonmalignant cells, thereby establishing a metabolite flow favorable to tumor progression. This metabolic adaptation of tumor cells further modulates the immune landscape, ultimately creating a tumor microenvironment characterized by drug resistance and immunosuppression. The synergistic regulation of energy and substance metabolic pathways might be a good antitumor therapeutic paradigm. However, due to the metabolic convergence, it is crucial to selectively modulate the aberrant metabolism of tumor cells without compromising the functionality of other cells. Small-molecule drugs have the ability to target a wide range of biomolecules for antitumor therapy, but their application is limited by undesirable toxicities. Constructing nanodrug delivery systems can improve their properties and allow for the inclusion of multiple drugs, thereby exerting synergistic antitumor effects. In this study, we developed a two-drug codelivery system using drugs-conjugated multibranched polymers to modulate tumor cell metabolism by exploiting synthetic lethal pathways for safe and effective antitumor therapy. By delivery of adapalene and erastin simultaneously through nanoparticles, the material and energy metabolism of tumor cells can be regulated. This nanoparticle construction achieves tumor tissue targeting and responsive drug release, alters metabolite flow within tumor cells, and effectively kills tumor cells. Additionally, the nanoparticles can reverse the tumor immunosuppressive microenvironment, starting from single-cell regulation to whole-lesion control.

Development of fresh solid phase extractant is critical for selective separation and purification of special proteins. Herein, we demonstrated a recombinant Staphylococcal Protein G (rSPG) with a His-tag modified the novel single-metal organic framework (rSPG@Ni-MOF-74). The proposed solid-phase extraction material possessed a uniform spindle-shaped structure, large surface area (709.60 m 2  g -1 ) and pore volume (0.08 m 3  g -1 ), high metal content (22.57 wt%), which facilitated the interaction between host and guest. As results, the composite displayed outstanding selective recognition and adsorption of IgG, due to synergistic effect of the binding ability of rSPG with the Fc region of IgG, maintained through hydrogen bonding and electrostatic attraction, as well as hydrophobic interaction. The adsorption performance and mechanism of rSPG@Ni-MOF-74 have been fully investigated. Additionally, the rSPG@Ni-MOF-74 composite could effectively separate IgG from serum obtained from healthy humans, with the purity of the separated IgG verified through SDS-PAGE analysis. Furthermore, LC-MS/MS analysis identified a high content of IgG (55.3 %) in the eluate from rSPG@Ni-MOF-74, suggesting the great potential of rSPG@Ni-MOF-74 in IgG separation and enrichment from complex matrix., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Conventional mini percutaneous nephrolithotomy (mPCNL) typically necessitates the pre-operative placement of ureteral catheters. With the development of enhanced recovery after surgery (ERAS), we introduce a novel approach: no ureteral catheter mini percutaneous nephrolithotomy (NUC-mPCNL). To evaluate the efficacy and safety of this innovative procedure compared to mPCNL, we compared the total operative time, stone clearance rate (SCR), stone-free rate (SFR), and complications among patients undergoing either modality from January to September 2021. Our findings revealed a statistically significant reduction in the mean total operative time for the NUC-mPCNL group (42.6 ± 2.4 vs. 60.2 ± 3.4 min, p < 0.001). The SCR, SFR and CSFR were comparable between two groups (98.5% vs. 97.8%, 84.3% vs. 76.0%, 64.7% vs. 60.0%, p = 0.337, 0.295, 0.625). WBC rise, hemoglobin drop and neutrophil percentage rise were similar in both groups. The overall complication rate in the NUC-mPCNL group was lower; however, the difference was not statistically significant (Clavien I, II and III; 11 vs. 13, 1 vs. 2 and 1 vs. 1). Consequently, we conclude that NUC-mPCNL effectively shortens the operative time and holds potential for expedited postoperative recovery., (© 2024. The Author(s).)

The weight of live pigs is directly related to their health, nutrition management, disease prevention and control, and the overall economic benefits to livestock enterprises. Direct weighing can induce stress responses in pigs, leading to decreased productivity. Therefore, modern livestock industries are increasingly turning to non-contact techniques for estimating pig weight, such as automated monitoring systems based on computer vision. These technologies provide continuous, real-time weight-monitoring data without disrupting the pigs' normal activities or causing stress, thereby enhancing breeding efficiency and management levels. Two methods of pig weight estimation based on image and point cloud data are comprehensively analyzed in this paper. We first analyze the advantages and disadvantages of the two methods and then discuss the main problems and challenges in the field of pig weight estimation technology. Finally, we predict the key research areas and development directions in the future.

Due to the limitations of current anti-HBV therapies, the HBV core (HBc or HBcAg) protein assembly modulators (CpAMs) are believed to be potential anti-HBV agents. Therefore, discovering safe and efficient CpAMs is of great value. In this study, we established a HiBiT-based high-throughput screening system targeting HBc and screened novel CpAMs from an in-house marine chemicals library. A novel lead compound 8a , a derivative of the marine natural product naamidine J, has been successfully screened for potential anti-HBV activity. Bioactivity-driven synthesis was then conducted, and the structure‒activity relationship was analyzed, resulting in the discovery of the most effective compound 11a (IC 50  = 0.24 μmol/L). Furthermore, 11a was found to significantly inhibit HBV replication in multiple cell models and exhibit a synergistic effect with tenofovir disoproxil fumarate (TDF) and IFNa2 in vitro for anti-HBV activity. Treatment with 11a in a hydrodynamic-injection mouse model demonstrated significant anti-HBV activity without apparent hepatotoxicity. These findings suggest that the naamidine J derivative 11a could be used as the HBV core protein assembly modulator to develop safe and effective anti-HBV therapies., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Authors.)

A novel amide alkaloid, bursatamide A (1), featuring an unprecedented propyl-hexahydronaphthalene carbon framework, was isolated from the infrequently studied sea hare Bursatella leachi, alongside a new 3-phenoxypropanenitrile alkaloid, bursatellin B (2), and twelve known compounds. The structures of 1 and 2 were elucidated through comprehensive spectroscopic data analyses, while their relative and absolute configurations (ACs) were established through total synthesis and a series of quantum chemical calculations, including calculated electronic circular dichroism (ECD) spectra, optical rotatory dispersion (ORD) methods, and DP4+ probability analyses. Bursatamide A (1) demonstrated inhibitory effects against the human pathogenic bacteria Listeria monocytogenes and Vibrio cholerae. Erythro-bursatellin B (21), a diastereoisomer of 2, exhibited notable antibacterial activity against the fish pathogenic bacterium Streptococcus parauberis FP KSP28, with an MIC 90 value of 0.0472 μg·mL -1 ., (Copyright © 2024 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.)

Immune checkpoint blockers (ICBs) therapy stands as the first-line treatment option for advanced renal cell carcinoma (RCC). However, its effectiveness is hindered by the immunosuppressive tumor microenvironment (TME). Sonodynamic therapy (SDT) generates tumor cell fragments that can prime the host's antitumor immunity. Nevertheless, the hypoxic microenvironment and upregulated autophagy following SDT often lead to cancer cell resistance. In response to these challenges, a hypoxia-responsive polymer (Poly(4,4'-azobisbenzenemethanol-PMDA)-mPEG 5k , P-APm) encapsulating both a HIF-2α inhibitor (belzutifan) and the ultrasonic sensitize (Chlorin e6, Ce6) is designed, to create the nanoparticle APm/Ce6/HIF. APm/Ce6/HIF combined with ultrasound (US) significantly suppresses tumor growth and activates antitumor immunity in vivo. Moreover, this treatment effectively transforms the immunosuppressive microenvironment from "immune-cold" to "immune-hot", thereby enhancing the response to ICBs therapy. The findings indicate that APm/Ce6/HIF offers a synergistic approach combining targeted therapy with immunotherapy, providing new possibilities for treating RCC., (© 2024 The Author(s). Advanced Healthcare Materials published by Wiley‐VCH GmbH.)

With a focus on a class of origami-inspired metamaterials, this work explores the role of panel confinement in their mechanical response under cyclic loading. The goal is twofold: (i) quantify the magnitude change in snapping force and energy dissipation attained by varying the severity of confinement of selected panels; and (ii) leverage insights to modulate in situ their mechanical response as dictated by a given application, hence propose panel confinement modulation as a practical design route for response reprogrammability. Through computational modelling, proof-of-concept fabrication and cyclic testing, we first identify and characterize the governing factors enabling either the alteration or the preservation of the snapping force magnitude during repeated cycles of forward and backward loading. Then, we demonstrate how the in situ modulation of the constrained distance between selected panels enables reprogramming their snapping sequence and energy dissipation. The results contribute to expanding the versatility and application of this class of origami metamaterial across sectors, from aerospace to protective equipment, requiring precise control of mechanical damping and energy dissipation.This article is part of the theme issue 'Origami/Kirigami-inspired structures: from fundamentals to applications'.

A solid-state electrochemiluminescence (ECL) sensor was fabricated by immobilizing luminol, a classical luminescent reagent, on a Zn-Co-ZIF carbon fiber-modified electrode for the rapid and sensitive detection of procymidone (PCM) in vegetable samples. The sensor was created by sequentially modifying the glassy carbon electrode with Zn-Co-ZIF carbon fiber (Zn-Co-ZIF CNFs), Pt@Au NPs, and luminol. Zn-Co-ZIF CNFs, prepared through electrospinning and high-temperature pyrolysis, possessed a large specific surface area and porosity, making it suitable as carrier and electron transfer accelerator in the system. Pt@Au NPs demonstrated excellent catalytic activity, effectively enhancing the generation of active substances. The ECL signal was significantly amplified by the combination of Zn-Co-ZIF CNFs and Pt@Au NPs, which can subsequently be diminished by procymidone. The ECL intensity decreased proportionally with the addition of procymidone, displaying a linear relationship within the concentration range 1.0 × 10 -13 to 1.0 × 10 -6 mol L -1 (R 2  = 0.993). The sensor exhibited a detection limit of 3.3 × 10 -14 mol L -1 (S/N = 3) and demonstrated outstanding reproducibility and stability, making it well-suited for the detection of procymidone in vegetable samples., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Background: Working memory refers to a process of temporary storage and manipulation of information to support planning, decision-making, and action. Frequently comorbid alcohol misuse and sleep deficiency have both been associated with working memory deficits. However, how alcohol misuse and sleep deficiency interact to impact working memory remains unclear. In this study, we aim to investigate the neural processes inter-relating alcohol misuse, sleep deficiency and working memory., Methods: We curated the Human Connectome Project (HCP) dataset and investigated the neural correlation of working memory in link with alcohol use severity and sleep deficiency in 991 young adults (521 women). The two were indexed by the first principal component (PC1) of principal component analysis of all drinking metrics and Pittsburgh Sleep Quality Index (PSQI) score, respectively. We processed the imaging data with published routines and evaluated the results with a corrected threshold. We used path model to characterize the inter-relationship between the clinical, behavioral, and neural measures, and explored sex differences in the findings., Results: In whole-brain regression, we identified β estimates of dorsolateral prefrontal cortex response (DLPFC β ) to 2- vs. 0-back in correlation with PC1. The DLPFC showed higher activation in positive correlation with PC1 across men and women (r=0.16, P<0.001). Path analyses showed the model PC1 → DLPFC β → differences in reaction time (2- minus 0-back; RT 2-0 ) of correct trials → differences in critical success index (2- minus 0-back; CSI 2-0 ) with the best fit. In women alone, in addition to the DLPFC, a cluster in the superior colliculus (SC) showed a significant negative correlation with the PSQI score (r=-0.23, P<0.001), and the path model showed the inter-relationship of PC1, PSQI score, DLPFC and SC β's, and CSI 2-0 in women., Conclusions: Alcohol misuse may involve higher DLPFC activation in functional compensation, whereas, in women only, sleep deficiency affects 2-back memory by depressing SC activity. In women only, path model suggests inter-related impact of drinking severity and sleep deficiency on 2-back memory. These findings suggest potential sex differences in the impact of drinking and sleep problems on working memory that need to be further investigated., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-24-156/coif). The authors have no conflicts of interest to declare., (2024 Quantitative Imaging in Medicine and Surgery. All rights reserved.)

Targeting the competitive-cooperative relationships among tumor cells and various immune cells can efficiently reverse the immune-dysfunction microenvironment to boost the immunotherapies for the triple-negative breast cancer treatment. Hence, a bacterial outer membrane vesicle-based nanocomplex is designed for specifically targeting malignant cells and immune cells to reconcile the relationships based on metabolic-immune crosstalk. By uniquely utilizing the property of charge-reversal polymers to realize function separation, the nanocomplexes could synergistically regulate tumor cells and immune cells. This approach could reshape the immunosuppressive competition-cooperation pattern into one that is immune-responsive, showcasing significant potential for inducing tumor remission in TNBC models., (© 2024 Wiley‐VCH GmbH.)

Background: Staphylococcus aureus is one of the most prevalent pathogens in bovine mastitis, which leads to substantial financial losses for the dairy industry., Results: In this study, S. aureus (n = 72) was isolated from 18 dairy farms in 15 provinces across China in 2021. The identification of these isolates at the species level was achieved by employing 16S rRNA sequencing. An isothermal amplification method for auxiliary detection of S. aureus was established, which can be employed not only for laboratory detection but also for point-of-care testing (POCT). Molecular characteristics of S. aureus mastitis in Chinese dairy cows were determined through MLST and spa typing. Finally, methicillin-resistant Staphylococcus aureus (MRSA) and MRSA resistance genes were detected using MIC and PCR amplification techniques. 72 isolates were identified as 12 sequence types (STs) and 7 clonal complexes (CC). ST1/CC1 was the dominant prevalent accounting for 33.3 % of the total, and exhibiting a wide distribution range. In terms of spa types, t114 was the dominant type, accounting for 31.9 % of the total, followed by t529 as the second major type. Four S. aureus strains were classified as MRSA according to their levels of oxacillin resistance (MIC ≥4 μg/mL). Among these four MRSA strains, one of them was found to be mecA positive. However, the presence of drug-resistance genes mecA and mecC was not detected in the remaining three MRSA strains, indicating the possible existence of new resistance genes., Conclusions: Our study investigated the prevalence of S. aureus mastitis in dairy cows in China, while also examined the molecular characteristics and MRSA strains. This information will help with the clinical monitoring, prevention, and control of S. aureus mastitis in dairy cattle., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Within the current process of large-scale dairy-cattle breeding, to address the problems of low recognition-accuracy and significant recognition-error associated with existing visual methods, we propose a method for recognizing the feeding behavior of dairy cows, one based on an improved RefineMask instance-segmentation model, and using high-quality detection and segmentation results to realize the recognition of the feeding behavior of dairy cows. Firstly, the input features are better extracted by incorporating the convolutional block attention module into the residual module of the feature extraction network. Secondly, an efficient channel attention module is incorporated into the neck design to achieve efficient integration of feature extraction while avoiding the surge of parameter volume computation. Subsequently, the GIoU loss function is used to increase the area of the prediction frame to optimize the convergence speed of the loss function, thus improving the regression accuracy. Finally, the logic of using mask information to recognize foraging behavior was designed, and the accurate recognition of foraging behavior was achieved according to the segmentation results of the model. We constructed, trained, and tested a cow dataset consisting of 1000 images from 50 different individual cows at peak feeding times. The method's effectiveness, robustness, and accuracy were verified by comparing it with example segmentation algorithms such as MSRCNN, Point&#95;Rend, Cascade&#95;Mask, and ConvNet&#95;V2. The experimental results show that the accuracy of the improved RefineMask algorithm in recognizing the bounding box and accurately determining the segmentation mask is 98.3%, which is higher than that of the benchmark model by 0.7 percentage points; for this, the model parameter count size was 49.96 M, which meets the practical needs of local deployment. In addition, the technologies under study performed well in a variety of scenarios and adapted to various light environments; this research can provide technical support for the analysis of the relationship between cow feeding behavior and feed intake during peak feeding periods.

In situ transcriptomic techniques promise a holistic view of tissue organization and cell-cell interactions. There has been a surge of multiplexed RNA in situ mapping techniques but their application to human tissues has been limited due to their large size, general lower tissue quality and high autofluorescence. Here we report DART-FISH, a padlock probe-based technology capable of profiling hundreds to thousands of genes in centimeter-sized human tissue sections. We introduce an omni-cell type cytoplasmic stain that substantially improves the segmentation of cell bodies. Our enzyme-free isothermal decoding procedure allows us to image 121 genes in large sections from the human neocortex in <10 h. We successfully recapitulated the cytoarchitecture of 20 neuronal and non-neuronal subclasses. We further performed in situ mapping of 300 genes on a diseased human kidney, profiled >20 healthy and pathological cell states, and identified diseased niches enriched in transcriptionally altered epithelial cells and myofibroblasts., (© 2024. The Author(s).)

Cancer metabolism plays multifaceted roles in the initiation and progression of tumors, and interventions in metabolism are considered fundamental approaches for cancer control. Within the vast metabolic networks of tumors, there exist numerous potential therapeutic targets, intricately interconnected with each other and with signaling networks related to immunity, metastasis, drug resistance, and more. Based on the characteristics of the tumor microenvironment, constructing drug delivery systems for multi-level modulation of the tumor microenvironment is proven as an effective strategy for achieving multidimensional control of cancer. Consequently, this article summarizes several features of tumor metabolism to provide insights into recent advancements in intelligent drug delivery systems for achieving multi-level regulation of the metabolic microenvironment in cancer, with the aim of offering a novel paradigm for cancer treatment., (© 2023 Wiley-VCH GmbH.)

Aim: Due to the diversity and complexity of tissues involved in secondary nasal deformities following unilateral cleft lip, secondary nasal deformity correction surgeries are challenging and often yield unsatisfactory results, posing a difficult problem for plastic surgeons. Autologous cartilage, with its low sculpting difficulty, minimal absorption, and stable tissue compatibility, is considered the optimal material for reconstructing the columella, nasal tip, and alar. This study analyzed the clinical outcomes of using autologous cartilage to create a Y-shaped columella to correct secondary nasal deformities after cleft lip surgery., Methods: In this retrospective study, 75 patients with secondary nasal deformity after unilateral cleft lip surgery were treated from January 2018 to December 2023. Appropriate costal cartilage, auricular cartilage, and iliac crest cartilage were fashioned into Y-shaped stents and implanted into the nasal columella of the patients to strengthen the tip cartilage. The free alar cartilage was sutured and fixed with a Y-shaped bracket. The wound healing rate, subjective satisfaction evaluation, and complications were analyzed. The nasal appearance, nasal deformity classification, and objective indices of healthy and affected nasal sides, function, and quality of life were compared before and after the operation., Results: All patients healed well during the first stage without related complications, and the average incision healing time was 5.16 ± 1.37 days. The scores of nasal tip position, nasal tip shape, nostril shape, nasal dorsum shape, and nasal floor shape at 6 months post-operation were significantly lower compared to pre-operation (p < 0.001). The grade of nasal deformity at 6 months post-operation was lower than the pre-operation (p < 0.001). Pre-operation, the nasal base and nasal width of the affected side were higher than those of the healthy side, while the nasal columellar and nostril height were lower (p < 0.001). At 6 months post-operation, the nasal base and nasal width decreased, and the nasal columellar and nostril height increased (p < 0.001), with no significant difference between the two sides (p > 0.05). The nasal obstruction symptom evaluation (NOSE) and Functional Rhinoplasty Outcome Inventory-17 (FROI-17) scores at 6 months post-operation were significantly lower than pre-operation, while the rhinoplasty outcome evaluation (ROE) score was higher (p < 0.001). The total patient satisfaction was 97.33% (73/75)., Conclusions: Y-shaped nasal columella made of autologous cartilage can effectively correct secondary nasal deformity after cleft lip surgery, improve nasal alar collapse, lengthen nasal columella, elevate nasal end, enhance the quality of life, nasal appearance, and nasal ventilation function of patients, with high satisfaction and few complications.

Purpose: To investigate prognostic values of prostatic urethra involvement (PUI) and construct a prognostic model that estimates the probability of cancer-specific survival for T1 bladder cancer patients., Method and Materials: We investigated the national Surveillance, Epidemiology, and End Results (SEER) database (2004-2015) to get patients diagnosed with T1 bladder cancer. An external validation cohort was obtained from the First Affiliated Hospital of Nanchang University. The Kaplan-Meier method with the log-rank test was applied to assess cancer-specific survival (CSS) and overall survival (OS). Moreover, the propensity score matching (PSM) and multivariable Cox proportional hazard model were performed. All patients were randomly divided into the development cohort and validation group at the ratio of 7:3. The performance of the model was internally validated by calibration curves and the concordance index (C-index)., Results: The PUI group had a lower survival rate of both CSS and overall survival OS before and after PSM when compared to non-involved patients (All P < 0.05). Multivariate analysis revealed a poor prognosis in the PUI group for cancer-specific mortality (CSM) and all-cause mortality (ACM) analyses before and after PSM (All P < 0.05). Seven variables, including age, surgery, radiotherapy, tumour size, PUI, and marital status, were incorporated in the final nomogram. The C-index in the development cohort was 0.715 (0.711-0.719), while it was 0.672 (0.667-0.677) in the validation group. Calibration plots for 3- and 5-year cancer-specific survival showed good concordance in the development and validation cohorts., Conclusions: PUI was an independent risk factor of ACM and CSM in T1 bladder cancer patients. In addition, a highly discriminative and precise nomogram that predicted the individualized probability of cancer-specific survival for patients with T1 bladder cancer was constructed., (© 2023. The Author(s).)

The tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC) is the main block for the penetration of chemotherapy. In the tumor microenvironment, a dense matrix composed of fibrin is formed on the exterior, while the interior is featured by high reduction, hypoxia and low pH. How to match the special microenvironment to on-demand drug release is the key to improve chemotherapeutic efficacy. Herein, a microenvironment-responsive micellar system is developed to deepen tumoral penetration. Briefly, the conjugation of a fibrin-targeting peptide to PEG-poly amino acid has been utilized to achieve accumulation of micelles in the tumor stroma. By modification of micelles with hypoxia-reducible nitroimidazole which becomes protonated under acidic conditions, their surface charge is more positive, facilitating deeper penetration into tumors. Paclitaxel was loaded onto the micelles via a disulfide bond to enable glutathione (GSH)-responsive release. Therefore, the immunosuppressive microenvironment is relived through the alleviation of hypoxia and depletion of GSH. Hopefully, this work could establish paradigms by designing sophisticated drug-delivery systems to tactfully employ and retroact the tamed tumoral microenvironment to improve the therapeutic efficacy based on understanding the multiple hallmarks and learning the mutual regulation. STATEMENT OF SIGNIFICANCE: Tumor microenvironment(TME) is an unique pathological feature of pancreatic cancer and an inherent barrier to chemotherapy. Numerous studies regard TME as the targets for drug delivery. In this work, we propose a hypoxia-responsive nanomicellar drug delivery system that aiming hypoxia TME of pancreatic cancer. The nanodrug delivery system could respond to the hypoxic microenvironment and enhance the penetration of the inner tumor at the same time preserving the outer tumor stroma, thus achieving targeted treatment of PDAC by preserving the integrity of the outer stroma. Simultaneously, the responsive group can reverse the degree of hypoxia in TME by disrupting the redox balance in the tumor region, thus achieving precise treatment of PDAC by matching the pathological characteristics of TME. We believe our article would provide new design ideas for the future treatments for pancreatic cancer., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Much is known about the generation, removal, and roles of 5-methylcytosine (5mC) in eukaryote DNA, and there is a growing body of evidence regarding N6-methyladenine, but very little is known about N4-methylcytosine (4mC) in the DNA of eukaryotes. The gene for the first metazoan DNA methyltransferase generating 4mC (N4CMT) was reported and characterized recently by others, in tiny freshwater invertebrates called bdelloid rotifers. Bdelloid rotifers are ancient, apparently asexual animals, and lack canonical 5mC DNA methyltransferases. Here, we characterize the kinetic properties and structural features of the catalytic domain of the N4CMT protein from the bdelloid rotifer Adineta vaga. We find that N4CMT generates high-level methylation at preferred sites, (a/c)CG(t/c/a), and low-level methylation at disfavored sites, exemplified by ACGG. Like the mammalian de novo 5mC DNA methyltransferase 3A/3B (DNMT3A/3B), N4CMT methylates CpG dinucleotides on both DNA strands, generating hemimethylated intermediates and eventually fully methylated CpG sites, particularly in the context of favored symmetric sites. In addition, like DNMT3A/3B, N4CMT methylates non-CpG sites, mainly CpA/TpG, though at a lower rate. Both N4CMT and DNMT3A/3B even prefer similar CpG-flanking sequences. Structurally, the catalytic domain of N4CMT closely resembles the Caulobacter crescentus cell cycle-regulated DNA methyltransferase. The symmetric methylation of CpG, and similarity to a cell cycle-regulated DNA methyltransferase, together suggest that N4CMT might also carry out DNA synthesis-dependent methylation following DNA replication., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interests with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Ventral striatum (VS) processes rewarding and punishing stimuli. Women and men vary in externalizing and internalizing traits, which may influence neural responses to reward and punishment. To investigate sex differences in how individual traits influence VS responses to reward and punishment, we curated the data of the Human Connectome Project and identified 981 (473 men) subjects evaluated by the Achenbach Adult Self-Report Syndrome Scales. We processed the imaging data with published routines and extracted VS response (β) to win and to loss vs. baseline in a gambling task for correlation with externalizing and internalizing symptom severity. Men vs. women showed more severe externalizing symptoms and higher VS response to monetary losses (VS-loss β) but not to wins. Men but not women showed a significant, positive correlation between VS-loss β and externalizing traits, and the sex difference was confirmed by a slope test. The correlations of VS-loss vs. externalizing and of VS-win vs. externalizing and those of VS-loss vs. externalizing and of VS-loss vs. internalizing traits both differed significantly in slope, confirming its specificity, in men. Further, the sex-specific relationship between VS-loss β and externalizing trait did not extend to activities during exposure to negative emotion in the face matching task. To conclude, VS responses to loss but not to win and their correlation with externalizing rather than internalizing symptom severity showed sex differences in young adults. The findings highlight the relationship of externalizing traits and VS response to monetary loss and may have implications for psychological models of externalizing behaviors in men., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

A long-standing paucity of effective therapies results in the poor outcomes of triple-negative breast cancer brain metastases. Immunotherapy has made progress in the treatment of tumors, but limited by the non-immunogenicity of tumors and strong immunosuppressive environment, patients with TNBC brain metastases have not yet benefited from immunotherapy. Dual immunoregulatory strategies with enhanced immune activation and reversal of the immunosuppressive microenvironment provide new therapeutic options for patients. Here, we propose a cocktail-like therapeutic strategy of microenvironment regulation-chemotherapy-immune synergistic sensitization and construct reduction-sensitive immune microenvironment regulation nanomaterials (SIL@T). SIL@T modified with targeting peptide penetrates the BBB and is subsequently internalized into metastatic breast cancer cells, releasing silybin and oxaliplatin responsively in the cells. SIL@T preferentially accumulates at the metastatic site and can significantly prolong the survival period of model animals. Mechanistic studies have shown that SIL@T can effectively induce immunogenic cell death of metastatic cells, activate immune responses and increase infiltration of CD8 + T cells. Meanwhile, the activation of STAT3 in the metastatic foci is attenuated and the immunosuppressive microenvironment is reversed. This study demonstrates that SIL@T with dual immunomodulatory functions provides a promising immune synergistic therapy strategy for breast cancer brain metastases., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Objective: To explore the advantages and disadvantages of robot-assisted laparoscopic adrenalectomy compared with retroperitoneal laparoscopic adrenalectomy., Methods: A total of 101 patients with adrenal tumors who received retroperitoneal laparoscopic adrenalectomy (RLA) (n=75) or robot-assisted laparoscopic adrenalectomy (RARLA) (n=26) in our hospital from January 2021 to December 2021 were retrospectively collected. Patients' demographics, tumor characteristics, and perioperative indicators were compared. Statistical analysis was performed using t-test for continuous variables and Pearson chi-square test or Fisher's exact test for categorical variables., Results: We found that blood loss in the RARLA group was significantly less than that in the RLA group (66.9 ± 35.5 ml vs 91.5 ± 66.1 ml, p = 0.020). Gastrointestinal function recovery time in RARLA group was significantly less than that in RLA group (19.9 ± 6.9 hours vs 32.0 ± 9.0 hours, p < 0.001). However, the operation time, drainage tube placement time, post-operative hospital stay in the RARLA group were significantly longer compared with the RLA group (149.6 ± 53.4 mins vs 118.7 ± 41.2 mins, p = 0.003; 4.9 ± 2.0 days vs 3.6 ± 1.1 days, p = 0.004; 6.4 ± 1.8 days vs 4.6 ± 1.6 days, p < 0.001). The hospitalization expense in the RARLA group is significantly higher than that in the RLA group (59284 ± 8724 RMB¥ vs 39785 ± 10126 RMB¥, p < 0.001). We found that there was no significant difference in the incidence of postoperative complications between the two groups. However, the pathological types of the two groups were significantly different. Patients in the RLA group had a higher proportion of adrenocortical adenoma, while patients in the RARLA group had a higher proportion of pheochromocytoma., Conclusion: Compared with traditional laparoscopic adrenalectomy, robot-assisted laparoscopic adrenalectomy can significantly reduce intraoperative blood loss and accelerate postoperative gastrointestinal recovery. It is committed to studying how to reduce the hospitalization time and hospitalization cost of RARLA, which can make RARLA more widely used., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Li, Xiao, Yu, Liu, Xi, Wang and Zhou.)

Objective: To compare the tumor control in prostate cancer patients with oligo-metastasis following combined robot-assisted radical prostatectomy and androgen deprivation versus androgen deprivation therapy alone based on total prostate-specific antigen (tPSA) assessment., Methods: Medical data of a total of 18 prostate cancer patients with oligometastasis administered in The First Affiliated Hospital of Nanchang University from March 2017 to March 2018 were prospectively collected. 10 patients received a combined therapy of robot-assisted radical prostatectomy and pharmaceutical androgen deprivation (RARP+ADT group), while 8 patients received pharmaceutical androgen deprivation therapy alone (ADT group). Then demographic characteristics, prostate volume, tumor characteristics and tPSA data were analysised and compared. Statistical analysis was performed using t-test for continuous variables and Pearson chi-square test or Fisher's exact test for categorical variables., Results: No significant difference was found in patients' age ( p = 0.075), prostate volume ( p = 0.134) and number of bone metastasis ( p = 0.342). Pre-treatment Gleason score was significantly lower in RA group ( p = 0.003). Patients in RARP+ADT group had significantly lower pre-treatment tPSA ( p = 0.014), while no statistical difference was noted in reexamined tPSA ( p = 0.140) on follow-up. No statistical difference was noted in tPSA decline rates (declined tPSA value per day) in RARP+ADT and ADT group (8.1 ± 4.7 verse 7.5 ± 8.0 ng/ml/d, p = 0.853). However, tPSA percentage decline rate (declined tPSA percentage per day) was significantly higher in RARP+ADT group (11.6 ± 1.5%/d verses 2.9 ± 2.2%/d, p < 0.001). Immediate urinary continence was achieved in 9 patients (90%) upon removal of urethral catheter on post-operative day 7 in RARP+ADT group., Conclusion: ADT alone and in combination with RARP both provide effective tumor control in patients suffering from prostate cancer with oligometastasis. ADT combined with RARP exhibited significant advantage in PSA percentage decline rate without compromising patients' urinary continence. Long-term tumor control requires further follow-up., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Li, Xi, Cheng, Yu, Zhang, Wang and Zhou.)

The PI3K-Akt-mTOR signaling pathway is a highly frequently activated signal transduction pathway in human malignancies, which has been a hot target for anti-tumoral drug discovery. Based on our previous research, a function-oriented synthesis (FOS) of imidazo[1,2-a]pyrazines and imidazo[1,2-b]pyridazines was conducted, and their anticancer activities in vitro and in vivo were evaluated. Among them, compound 42 exhibited excellent dual PI3K/mTOR inhibitory activity, with IC 50 values on PI3Kα and mTOR of 0.06 nM and 3.12 nM, respectively, much better than our previous reported compound 15a. Furthermore, compound 42 exhibited significant in vitro and in vivo anti-tumoral activities, great kinase selectivity, low hepatotoxicity, modest plasma clearance and acceptable oral bioavailability, which is a promising PI3K/mTOR targeted anti-cancer drug candidate., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Objective: To compare the efficacy and safety between conservative treatment and surgery for the patients with small (1-3cm) nonfunctional adrenal incidentaloma (NFAI)., Methods: The patients with small (1-3cm) NFAI who received conservative treatment or surgery in our hospital from November 2018 to December 2019 were retrospectively collected. A total of 83 patients were included in this study. They were divided into two groups according to the treatment methods: the surgery group (n=51) and the conservative treatment group (n=32).Then patients' demographics, tumor characteristics, functional indicators and complications were compared. Statistical analysis was performed using t-test for continuous variables and Pearson chi-square test or Fisher's exact test for categorical variables., Results: At the time of diagnosis, after 3 months, after 6 months, after 12 months, and after 24 months, we found that there was no significant difference between the two groups in systolic blood pressure, diastolic blood pressure, serum potassium levels, and hormone levels. 51 patients chose to have surgery, of which 41 patients chose RLA and 10 patients chose RARLA. RARLA group patients had the highest total cost and conservative treatment group patients had the lowest cost, and the difference was significant (P < 0.001). There was no significant difference in tumor size in the conservative treatment group between at the time of diagnosis and after 24 months (P = 0.305)., Conclusion: Surgical treatment is more effective for 1-3cm NFAI, but conservative treatment is safer and more economical. Follow-up after conservative or surgical treatment is necessary., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Li, Xiao, Zhan, Yu, Zhang, Xi, Wang and Zhou.)

Objectives: To investigate the outcome and safety of retroperitoneal laparoscopic partial adrenalectomy in the treatment of nonfunctional unilateral adrenal tumors in the day surgery mode., Methods: Nineteen patients bearing nonfunctional unilateral 20-40 mm adrenal tumors were prospectively enrolled and underwent retroperitoneal laparoscopic partial adrenalectomy in the day surgery unit of our hospital between June 2021 and March 2022. All patients were diagnosed with non-functional adrenal tumors as outpatients before being admitted to the day surgery unit with their consent. Patient demographics and perioperative data were prospectively documented. The patients were followed up by telephone on day 1, 3 and 7 after discharge and followed up for 6 months., Results: The patient's age was 50.5 ± 11.9 yr (range from 19.0 - 69.0). Seven patients were female. Twelve patients underwent surgery on the left side. The maximal diameter of tumor was 28.3 ± 5.7 mm (20.0 - 40.0 mm). Operation time was 72.1 ± 14.9 min (58.0 - 120.0 min). Mean blood loss was 64.7 ± 50.4 ml (30.0 - 200.0 ml). The gastrointestinal function recovery time was 9.7 ± 2.6 h (6.0 - 16.0 h). Retroperitoneal drainage was removed 24.8 ± 13.3 h (range 18.0 - 72.0) after surgery. Four patients were transferred to the general ward for postoperative management, while others were discharged within 24 hours after surgery. Length of hospital stay was 48.8 ± 13.1 h (38.0 - 85.0h). Hospitalization expense was 24168.4 ± 2910.3 RMB¥ (20844.3 - 34369.8 RMB¥). Postoperative pathology revealed 17 cortical adenoma, 1 pheochromocytoma and 1 lymphatic duct tumor., Conclusion: Retroperitoneal laparoscopic partial adrenalectomy for nonfunctional unilateral adrenal tumors in the day surgery mode is safe when strict selection criteria and perioperative management protocol are followed, which has the potential to shorten length of hospital stay and reduce lower hospitalization costs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Xi, Yu, Liu, Zhu, Gong, Fu, Wang and Zhou.)

Background: Asthma is a heterogeneous disorder of the airways related to inflammation; it affects millions of people worldwide. Due to the side effects of inhaled corticosteroids, researchers focused on the therapeutic effects of compounds derived from natural products., Objective: To investigate the therapeutic benefits of Narirutin a valuable flavonoid in Citri Reticulatae Pericarpium for asthma., Methods: Narirutin was extracted using the enzyme-assisted method with the L9 (34) orthogonal array to optimize the temperatures, pH, and reaction time. The mechanism of action of Narirutin was investigated via ELISA, flow cytometry, and Western blot analysis in vivo., Results: Narirutin suppressed inflammatory cell infiltration in the lung tissue and decreased IgE and IgG1 levels in serum in vivo. It can also alleviate interleukin (IL)-4, IL-5, and interferon-γ concentrations in bronchoalveolar lavage fluid in mice. Moreover, it increased the ratio of CD4+/CD8+ T cells. Additionally, Narirutin significantly suppressed p-ERK1/2 and p-JNK expression in the MAPK signaling pathway., Conclusion: Narirutin affects the Th1/Th2 imbalance through the p-ERK and p-JNK suppression in the MAPK signaling pathway.

Objectives: To propose an original and standardized scoring system to quantify the functional and anatomical characteristics of adrenal tumor., Materials and Methods: Four groups of consecutive adrenalectomies (n = 458) with heterogeneity in tumor characteristics and surgical approaches, including 212 laparoscopic cases (Group 1) and 105 robotic cases (Group 2) from The First Affiliated Hospital of Nanchang University, 28 robotic cases from Temple University Hospital (Group 3) and 113 laparoscopic cases from The First Affiliated Hospital of Guangxi Medical University (Group 4). All patients were followed up for 4.5 to 5.5 years. Six parameters including functional status or suspicion of malignancy, tumor size, relationship to adjacent organs, intratumoral enhancement on CT, nearness of the tumor to major vessels and body mass index were assessed and scored on a 0, 1 and 2 points scale. Correlation between the sum of the 6 scores and tumor laterality (ADRENAL score) verse operative time (OT), estimated blood loss (EBL), perioperative complications, transfusion, conversion and length of hospital stay was analyzed., Results: ADRENAL score was a strong predictor of both OT and EBL in all four groups (p < 0.05 for all tests). In Group 2 and 4, higher ADRENAL score seemed to correlate with longer hospital stay. No statistically significant correlation between ADRENAL score and complication, transfusion or conversion was noted yet., Conclusions: ADRENAL score appears to be a valid predictor of surgical outcomes. It may provide a common reference for adrenal surgery training program, preoperative risk assessment and stratified comparative analysis of adrenal surgeries via different techniques and approaches., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhou, Li, Fu, Liu, Zhang, Xia, Gong, Zhu, Lei, Kaplan, Deng, Eun and Wang.)

Background: Hypertensive disorders in pregnancy (HDP) are diseases that coexist with pregnancy and hypertension. The pathogenesis of this disease is complex, and different physiological and pathological states can develop different subtypes of HDP., Objective: To investigate the predictive effects of different variable selection and modeling methods on four HDP subtypes: gestational hypertension, early-onset preeclampsia, late-onset preeclampsia, and chronic hypertension complicated with preeclampsia., Methods: This research was a retrospective study of pregnant women who attended antenatal care and labored at Beijing Maternity Hospital, Beijing Haidian District Maternal and Child Health Hospital, and Peking University People's Hospital. We extracted maternal demographic data and clinical characteristics for risk factor analysis and included gestational week as a parameter in this study. Finally, we developed a dynamic prediction model for HDP subtypes by nonlinear regression, support vector machine, stepwise regression, and Lasso regression methods., Results: The AUCs of the Lasso regression dynamic prediction model for each subtype were 0.910, 0.962, 0.859, and 0.955, respectively. The AUC of the Lasso regression dynamic prediction model was higher than those of the other three prediction models. The accuracy of the Lasso regression dynamic prediction model was above 85%, and the highest was close to 92%. For the four subgroups, the Lasso regression dynamic prediction model had the best comprehensive performance in clinical application. The placental growth factor was tested significant ( P  < 0.05) only in the stepwise regression dynamic prediction model for early-onset preeclampsia., Conclusion: The Lasso regression dynamic prediction model could accurately predict the risk of four HDP subtypes, which provided the appropriate guidance and basis for targeted prevention of adverse outcomes and improved clinical care., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 Zhang, Xu, Yang, Sun, Liu, Lian, Li, Hao, Yang and Li.)

Pre-eclampsia (PE) is a type of hypertensive disorder during pregnancy, which is a serious threat to the life of mother and fetus. It is a placenta-derived disease that results in placental damage and necrosis due to systemic small vessel spasms that cause pathological changes such as ischemia and hypoxia and oxidative stress, which leads to fetal and maternal damage. In this study, four types of risk factors, namely, clinical epidemiology, hemodynamics, basic biochemistry, and biomarkers, were used for the initial selection of model parameters related to PE, and factors that were easily available and clinically recognized as being associated with a higher risk of PE were selected based on hospital medical record data. The model parameters were then further analyzed and screened in two subgroups: early-onset pre-eclampsia (EOPE) and late-onset pre-eclampsia (LOPE). Dynamic gestational week prediction model for PE using decision tree ID3 algorithm in machine learning. Performance of the model was: macro average (precision = 76%, recall = 73%, F1-score = 75%), weighted average (precision = 88%, recall = 89%, F1-score = 89%) and overall accuracy is 86%. In this study, the addition of the dynamic timeline parameter "gestational week" made the model more convenient for clinical application and achieved effective PE subgroup prediction., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Xu, Sun, Jia, Yang, Liu, Hao, Zhang, Yang, Li, Zhang and Lian.)

A new intervention was investigated for the induction of oral tolerance (OT) of OVA using narirutin by in vivo and in vitro experiments combined with network pharmacology and structural analysis of molecular docking. Narirutin (and its metabolism naringenin) has effects on OT by affecting B cell function, DCs, and T cell response by prediction. It was verified that narirutin could affect B cell function of secreting antibodies, thereby reducing the ability of DCs to absorb antigens by affecting GATA3, CCR7, STAT5, and MHCII expression and regulating T cell response by suppressing Th2 and improving Treg cells in vivo . Molecular docking showed that steric hindrance effects may be the reason for weaker binding energy with targets of narirutin. However, this does not mean that it has no bioactivity, for it can inhibit mast cell degranulation. This finding is interesting because it offers the possibility of using natural compounds to promote oral tolerance.

Background: This study analyzed the influencing factors of fetal growth restriction (FGR), and selected epidemiological and fetal parameters as risk factors for FGR., Objective: To establish a dynamic prediction model of FGR., Methods: This study used two methods, support vector machine (SVM) and multivariate logistic regression, to establish the prediction model of FGR at different gestational weeks., Results: At 20-24 weeks and 25-29 weeks of gestation, the effect of the multivariate Logistic method on model prediction was better. At 30-34 weeks of gestation, the prediction effect of FGR model using the SVM method is better. The ROC curve area was above 85%., Conclusions: The dynamic prediction model of FGR based on SVM and logistic regression is helpful to improve the sensitivity of FGR in pregnant women during prenatal screening. The establishment of prediction models at different gestational ages can effectively predict whether the fetus has FGR, and significantly improve the clinical treatment effect., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 Lian, Wang, Bao, Yang, Liu, Hao, Zhang, Yang, Li, Meng, Zhang and Li.)

Breast-to-brain metastatic cells can interact with the surrounding cells, including astrocytes and microglia, to generate a pro-tumorigenic niche. Breast-to-brain metastasis can be treated using a dual strategy of eliminating metastatic tumor cells and normalizing their localized microenvironment. The effective accumulation of drugs at the action site of metastasis is crucial to realizing the above strategy, especially when dealing with the blood-brain barrier (BBB)-penetrating and tumor-targeting tactics. Here, we establish an in-situ microenvironment-tailored micelle (T-M/siRNA) to co-deliver therapeutic siRNA and paclitaxel (PTX) into the breast-to-brain metastasis. Anchored with a D-type cyclic peptide, T-M/siRNA can penetrate the BBB and subsequently target the brain metastases. Upon internalization by metastatic tumor cells, T-M/siRNA can release PTX in the high-level glutathione (GSH), resulting in killing cancer cells. Meanwhile, the micellar structure is dissociated, resulting in lowering the charge density to release the loaded siRNA that can targeted downregulate the expression of protocadherin 7 (PCDH7). Treatment of model mice revealed that T-M/siRNA can inhibit the abnormal activation of astrocytes and immunosuppressive activation of microglia, resulting in significantly enhanced synergistic anti-tumor efficacy. This study indicates that the micelle system can serve as a hopeful strategy to treat breast-to-brain metastasis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Indole compounds are widely found in natural products and drug candidates. The transition-metal-catalyzed regioselective C-H bond functionalization of indoles as the most efficient method for the synthesis of various functionalized indoles has been extensively studied in the past two decades due to its advantages of step economy and atom economy. In general, the catalysts included the transition-metals (Pd, Rh, Ru, Cu, Co, Fe, Zn, and Ga) and these reactions were accomplished with a remarkably wide range of coupling reagents for construction of various C-C and C-X (X = N, O, S) bonds. However, the general and important rules of the regioselectivity are not clear to date. Therefore, a comprehensive analysis through previous reported theoretical studies on transition-metal-catalyzed regioselective C-H bond functionalization of indoles was crucial and significant. In this review, we found that when the C-H bond activation process was the rate-determining step, the regioselectivity ordinarily occurred at the C7 or C4 positions (on benzene ring), and otherwise, the regioselectivity often occurred at C2 position (on pyrrole ring). For indoline substrates, the C-H bond functionalization occurred at the benzene ring. General rules of the regioselectivities for transition-metal-catalyzed C-H bond functionalization of indoles. This review collects major advances in the transition-metal-catalyzed C-H bond functionalization of indoles and indolines., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The compact extracellular matrix (ECM) of pancreatic ductal adenocarcinoma (PDAC) is the major physical barrier that hinders the delivery of anti-tumor drugs, leading to strong inherent chemotherapy resistance as well as establishing an immunosuppressive tumor microenvironment (TME). However, forcibly destroying the stroma barrier would break the balance of delicate signal transduction and dependence between tumor cells and matrix components. Uncontrollable growth and metastasis would occur, making PDAC more difficult to control. Hence, we design and construct an aptamer-decorated hypoxia-responsive nanoparticle s(DGL) n @Apt co-loading gemcitabine monophosphate and STAT3 inhibitor HJC0152. This nanoparticle can reverse its surficial charge in the TME, and reduce the size triggered by hypoxia. The released ultra-small DGL particles loading gemcitabine monophosphate exhibit excellent deep-tumor penetration, chemotherapy drugs endocytosis promotion, and autophagy induction ability. Meanwhile, HJC0152 inhibits overactivated STAT3 in both tumor cells and tumor stroma, softens the stroma barrier, and reeducates the TME into an immune-activated state. This smart codelivery strategy provides an inspiring opportunity in PDAC treatment., (Copyright © 2022. Published by Elsevier Ltd.)

It is critical to characterize changes in the structure and composition of the host fungal community in natural Cryptosporidium infection, because it gives the possible overview of gut microbiome in host homeostasis and disease progression. A total of 168 rectal fecal samples were collected and examined using nPCR. The positive samples were double-checked using 18S rDNA high-throughput sequencing. After confirmation, ITS high-throughput sequencing was utilized to investigate the fungal community's response to natural Cryptosporidium infection. Results showed that a total of three positive samples (1.79%) were identified with an increased abundance of fungi associated with health hazards, such as class Dothideomycetes, families, i.e., Cladosporiaceae, Glomerellaceae, and genera, i.e., Wickerhamomyces , Talaromyces , Cladosporium , Dactylonectria , and Colletotrichum . On the contrary, taxa associated with favorable physiological effects on the host were shown to have the reverse impact, such as families, i.e., Psathyrellaceae, Pseudeurotiaceae and genera ( Beauveria , Nigrospora , and Diversispora ). For the first time, we evaluated the condition of natural Cryptosporidium infection in horses in Wuhan, China, and discovered distinct variations in the fungal microbiome in response to natural infection. It might prompt a therapy or prevention strategy to apply specific fungal microorganisms that are probably responsible for decreased susceptibility or increased resistance to infection., Competing Interests: KD was employed by China Tobacco Henan Industrial Co., Ltd., China. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Li, Chen, Kulyar, Duan, Li, Bhutta, Wu and Li.)

Pyriproxyfen (PPF) mimics a natural hormone in insects and disrupts their growth. It is a well-known synthetic insecticide and aromatic juvenile hormone analog frequently used in agriculture and vegetable crops to control various insect species. At present, scanty information is available about the possible potential threats of PPF in aquatic organisms. Therefore, in this study, different toxico-pathologic endpoints of PPF like DNA damage, biomarkers of oxidative stress, and status of antioxidant enzymes were determined in Labeo rohita (freshwater fish). In our study, 60 active, free from any external obvious ailments, same size, age, and body mass were randomly allocated to four glass aquaria (T0-T3) separately containing 100 L water. The fish present in groups T1, T2, and T3 were administered PPF dissolved in water 300, 600, and 900  μ g/L for 30 days. Different tissues including the blood and visceral organs were obtained from each fish on days 10, 20, and 30 of the experiment. Results on various morphological and nuclear changes in red blood cells of PPF-exposed Labeo rohita fish including pear-shaped erythrocytes, spherocytes, red blood cells with a blebbed nucleus, micronucleus, and nuclear remnants were significantly increased. Our results on genotoxicity (comet assay) recorded significantly ( P ≤ 0.05) increased DNA damage in various tissues of insecticide-exposed fish. The results on oxidative stress profile (reactive oxygen species and thiobarbituric acid reactive substances) and antioxidant enzymes (reduced glutathione superoxide dismutase, peroxidase, and catalase) in multiple tissues of Labeo rohita fish concluded significantly ( P ≤ 0.05) higher quantity of biomarkers of oxidative stress and lower concentrations of different antioxidant enzymes in treated fish. Hence, the findings of our experimental research determine that PPF could induce adverse toxic impacts on multiple tissues of Labeo rohita fish., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2022 Xuwen Li et al.)

DNA methylation plays vital roles in both prokaryotes and eukaryotes. There are three forms of DNA methylation in prokaryotes: N 6 -methyladenine (6mA), N 4 -methylcytosine (4mC), and 5-methylcytosine (5mC). Although many sequencing methods have been developed to sequence specific types of methylation, few technologies can be used for efficiently mapping multiple types of methylation. Here, we present NT-seq for mapping all three types of methylation simultaneously. NT-seq reliably detects all known methylation motifs in two bacterial genomes and can be used for identifying de novo methylation motifs. NT-seq provides a simple and efficient solution for detecting multiple types of DNA methylation., (© 2022. The Author(s).)

Background: The surgical treatment of complex acetabular fractures is one of the most challenging procedures for orthopedic surgeons. The Pararectus approach, as a reasonable alternative to the existing surgical procedures, was performed for the treatment of acetabular fractures involving the anterior column. This study aimed to evaluate outcome using the Pararectus approach for acetabular fractures involving anterior columns., Methods: Thirty-seven with displaced acetabular fractures involving anterior columns were treated between July 2016 and October 2019 using the Pararectus approach. The functional outcomes (using the Merle d Aubigné and Postel scoring system, WOMAC and modified Harris scoring), the quality of surgical reduction (using the Matta criteria), and postoperative complications were assessed during approximately 26 months follow-up period., Results: Thirty-seven patients (mean age 53 years, range: 30-71; 28 male) underwent surgery. Mean intraoperative blood loss was 840 ml (rang: 400-2000 ml) and mean operating time was 210 min (rang: 140-500 min). The modified Merle d Aubigné score was excellent and good in 27 cases (73%), fair in 6 cases (16%), and poor in 3 cases (11%). The mean score was 88.5 (range:77-96) for the modified Harris Hip scores, and 22 (range:7-35) for the WOMAC scores after operation. Postoperative functional outcomes were significantly improved compared with preoperative outcomes (P < 0.0001). The quality of reduction was anatomical in 21 cases (57%), satisfactory in 9 cases (24%), and unsatisfactory in 7 cases (19%). At follow-up, four patients developed a DVT, and heterotopic bone formation was observed in one patient. The hip osteoarthritis was not observed., Conclusion: The Pararectus approach achieved good functional outcomes and anatomical reduction in the treatment of acetabular fractures involving anterior column with minimal access morbidity., (© 2022. The Author(s).)

The extraction of Scutellaria baicalensis Georgi was investigated using the response surface methodology-genetic algorithm mathematical regression model, and the extraction variables were optimized to maximize the flavonoid yield. Furthermore, a simple and efficient ultrafiltration-liquid chromatography-mass spectrometry and molecular docking methods were developed for the rapid screening and identification of acetylcholinesterase inhibitors present in Scutellaria baicalensis Georgi. Subsequently, four major chemical constituents, namely baicalein, norwogonin, wogonin, and oroxylin A, were identified as potent acetylcholinesterase inhibitors. This novel approach, involving the use of ultrafiltration-liquid chromatography-mass spectrometry and molecular docking methods combined with stepwise flow rate counter-current chromatography and semi-preparative high-performance liquid chromatography, could potentially provide a powerful tool for the screening and extraction of acetylcholinesterase inhibitors from complex matrices and be a useful platform for the production of bioactive and nutraceutical ingredients., (© 2022 Wiley-VCH GmbH.)

The rapid postoperative recurrence and short survival time of glioblastoma (GBM) patients necessitate immediate and effective postoperative treatment. Herein, an immediate and mild postoperative local treatment strategy is developed that regulates the postoperative microenvironment and delays GBM recurrence. Briefly, an injectable hydrogel system (imGEL) loaded with Zn(II) 2 -AMD3100 (AMD-Zn) and CpG oligonucleotide nanoparticles (CpG NPs) is injected into the operation cavity, with long-term function to block the recruitment of microglia/ macrophages and activate cytotoxic T cells. The finding indicated that the imGEL can regulate the immune microenvironment, inhibit GBM recurrence, and gain valuable time for subsequent adjuvant clinical chemotherapy., (© 2022 Wiley-VCH GmbH.)

Glutathione (GSH) is an important antioxidant and free radical scavenger that converts harmful toxins into harmless substances and excretes them out of the body. In this paper, 3D hierarchical flower-like nanozyme named MnO 2 /PS (polystyrene) was successfully prepared by template method for the first time. After the systematical studies, MnO 2 /PS nanozyme was evaluated to possess favorable oxidase activity and direct 3,3',5,5'-tetramethylbenzidine (TMB) catalytic ability in the near-neutral environment at room temperature. With the addition of different concentrations of GSH, oxidized TMB can be reduced to TMB with the whole process from blue to nearly colorless be observed by naked eyes. In addition, there is a good linear relationship in the range 1-50 μM and a detection limit of 0.08 μM. The method proposed can be successfully applied to the detection of reduced GSH in tablets and injections with good selectivity and high sensitivity. The analysis results exhibited good consistency with the results obtained by HPLC., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Glutathione (GSH) is an important antioxidant and free radical scavenger that converts harmful toxins into harmless substances and excretes them out of the body. In the present study, we successfully prepared single-atom iron oxide-nanoparticle (Fe-NP)-modified nanodiamonds (NDs) named Fe-NDs via a one-pot in situ reduction method. This nanozyme functionally mimics two major enzymes, namely, peroxidase and oxidase. Accordingly, a colorimetric sensing platform was designed to detect hydrogen peroxide (H 2 O 2 ) and GSH. Owing to their peroxidase-like activity, Fe-NDs can oxidize colorless 3,3',5,5'-tetramethylbenzidine (TMB) into blue with sufficient linearity at H 2 O 2 concentrations of 1-60 μM and with a detection limit of 0.3 μM. Furthermore, using different concentrations of GSH, oxidized TMB can be reduced to TMB, and the color change from blue to nearly colorless can be observed by the naked eye (linear range, 1-25 μM; detection limit, 0.072 μM). The established colorimetric method based on oxidase-like activity can be successfully used to detect reduced GSH in tablets and injections with good selectivity and high sensitivity. The results of this study exhibited reliable consistency with the detection results obtained using high-performance liquid chromatography (HPLC). Therefore, the Fe-NDs colorimetric sensor designed in this study offers adequate accuracy and sensitivity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Liu, Yan, Huang, Sun, Zhang, Fu, Li and Jin.)

Background: Gestational diabetes mellitus (GDM) is a metabolic disease that seriously endangers the health of mothers and children. It is important to monitor GDM in real-time before diagnosis and to prevent it effectively., Objective: GDM was divided into the second trimester diagnosed diabetes mellitus (GDM&#95;24) and the third trimester diagnosed diabetes mellitus (GDM&#95;30). The risk prediction of two types of GDM was performed in normal pregnant women at 11-13 and 16-19 weeks of pregnancy, respectively., Methods: By stages, the K-W test was used to analyze the differences between basic information and energy metabolism factors, and multiple logistic regression was used to analyze the risk of energy metabolism factors and to correct the confounders with significant differences., Results: For the GDM&#95;24 group, each additional unit of oxygen consumption (VO2), carbon dioxide production, and resting energy expenditure (REE) increased the risk by 2.4%, 3.5%, 0.4%, and 2.1%, 2.6%, and 0.3%, respectively, at 11-13 and 16-19 weeks of pregnancy. For the GDM&#95;30 group, each additional unit of VO2 and REE was associated with an increased risk of 2.3% and 0.3%, respectively, at 16-19 weeks of pregnancy., Conclusion: The risk of GDM&#95;30 only appeared in pregnant women during 16-19 weeks of pregnancy, which may indicate that GDM&#95;24 and GDM&#95;30 have different pathogenesis.

N 6 -methyladenine (N 6 -mA, m 6 dA, or 6mA), a prevalent DNA modification in prokaryotes, has recently been identified in higher eukaryotes, including mammals. Although 6mA has been well-studied in prokaryotes, the function and regulatory mechanism of 6mA in eukaryotes are still poorly understood. Recent studies indicate that 6mA can serve as an epigenetic mark and play critical roles in various biological processes, from transposable-element suppression to environmental stress response. Here, we review the significant advances in methodology for 6mA detection and major progress in understanding the regulation and function of this non-canonical DNA methylation in eukaryotes, predominantly mammals., (© 2021. The Author(s).)

Reperfusion injury is still a major challenge that impedes neuronal survival in ischemic stroke. However, the current clinical treatments are remained on single pathological process, which are due to lack of comprehensive neuroprotective effects. Herein, a macrophage-disguised honeycomb manganese dioxide (MnO 2 ) nanosphere loaded with fingolimod (FTY) is developed to salvage the ischemic penumbra. In particular, the biomimetic nanoparticles can accumulate actively in the damaged brain via macrophage-membrane protein-mediated recognition with cell adhesion molecules that are overexpressed on the damaged vascular endothelium. MnO 2 nanosphere can consume excess hydrogen peroxide (H 2 O 2 ) and convert it into desiderated oxygen (O 2 ), and can be decomposed in acidic lysosome for cargo release, so as to reduce oxidative stress and promote the transition of M1 microglia to M2 type, eventually reversing the proinflammatory microenvironment and reinforcing the survival of damaged neuron. This biomimetic nanomedicine raises new strategy for multitargeted combined treatment of ischemic stroke., (© 2021 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Metabolic interactions between different cell types in the tumor microenvironment (TME) often result in reprogramming of the metabolism to be totally different from their normal physiological processes in order to support tumor growth. Many studies have attempted to inhibit tumor growth and activate tumor immunity by regulating the metabolism of tumors and other cells in TME. However, metabolic inhibitors often suffer from the heterogeneity of tumors, since the favorable metabolic regulation of malignant cells and other cells in TME is often inconsistent with each other. Therefore, we reported the design of a pH-sensitive drug delivery system that targets different cells in TME successively. Outer membrane vesicles (OMVs) derived from Gram-negative bacteria were applied to coload paclitaxel (PTX) and regulated in development and DNA damage response 1 (Redd1)-siRNA and regulate tumor metabolism microenvironment and suppress tumor growth. Our siRNA@M-/PTX-CA-OMVs could first release PTX triggered by the tumor pH (pH 6.8). Then the rest of it would be taken in by M2 macrophages to increase their level of glycolysis. Great potential was observed in TAM repolarization, tumor suppression, tumor immune activation, and TME remolding in the triple-negative breast cancer model. The application of the OMV provided an insight for establishing a codelivery platform for chemical drugs and genetic medicines.

Current therapeutic strategies for Alzheimer's disease (AD) treatments mainly focus on β-amyloid (Aβ) targeting. However, such therapeutic strategies have limited clinical outcomes due to the chronic and irreversible impairment of the nervous system in the late stage of AD. Recently, inflammatory responses, manifested in oxidative stress and glial cell activation, have been reported as hallmarks in the early stages of AD. Based on the crosstalk between inflammatory response and brain cells, a reactive oxygen species (ROS)-responsive dendrimer-peptide conjugate (APBP) is devised to target the AD microenvironment and inhibit inflammatory responses at an early stage. With the modification of the targeting peptide, this nanoconjugate can efficiently deliver peptides to the infected regions and restore the antioxidant ability of neurons by activating the nuclear factor (erythroid-derived 2)-like 2 signaling pathway. Moreover, this multi-target strategy exhibits a synergistic function of ROS scavenging, promoting Aβ phagocytosis, and normalizing the glial cell phenotype. As a result, the nanoconjugate can reduce ROS level, decrease Aβ burden, alleviate glial cell activation, and eventually enhance cognitive functions in APPswe/PSEN1dE9 model mice. These results indicate that APBP can be a promising candidate for the multi-target treatment of AD., (© 2021 Wiley-VCH GmbH.)

Context: It is an efficient strategy to apply inhibition of mast cell degranulation for evaluating anti-allergic effects of compounds. Previous works confirmed that narirutin had anti-allergic activity in OVA induced allergic asthma murine model. However, the mechanism is not clear. Objective: Here, inhibitory mechanism of narirutin on RBL-2H3 cells degranulation was investigated. Materials and methods: Cell viability was analyzed by CCK-8 kits, cell degranulation was analyzed by ELISA methods, morphology and ultrastructure of cells was observed by atomic force microscopy, intracellular Ca 2+ concentration was measured by fluorescence microscopre, mRNA expression were measured by PCR, and signaling pathways were measured by WB. Results: The results showed that narirutin have no direct effects on mRNA expression of FcεRI subunit. However, it inhibited Ca 2+ influx by suppressing the phosphorylation of Syk, LAT and PLCγ1 signaling pathway transduction. Subsequently, the inhibition of Ca 2+ influx directly leads to NF-κB signaling pathway transduction decreased. Narirutin can also suppress the phosphorylation of MAPK signaling pathways by decreasing the expression of P-p38, P-ERK and P-JNK, inhibit the synergistic effect for Ca 2+ influx, and then reduce the release of IL-4, TNF-α, histamine and β-HEX. Conclusion: Our study suggested that the inhibitory mechanism of narirutin on RBL-2H3 cells degranulation could be related to regulate MAPK, NF-κB and Tyrosine kinase signaling pathway.